The ability to see is dependent on the actions of several structures in and around the eye. When one focuses on an object, light rays are reflected from the object to the cornea. The light rays are then bent, refracted and focused by the cornea into the eyeball, through the lens and finally to the retina. The cornea is the main refractive element in the eye and is responsible for 75-80% of the focussing of light onto the retina. The retina then converts light into electrical impulses which are transmitted through the optic nerve to the brain where the image is perceived. The cornea is a highly organised structure being composed of 3 cellular layers—an external multilayered epithelium, middle stroma, and inner corneal endothelium. The acellular largely collagenous Bowman's membrane underlies the epithelium and is often considered the anterior most portion of the stroma. Between the stroma and endothelium, lies a thinner acellular layer, the Descemet's membrane.
There are a large number of diseases and conditions that affect the function of the cornea requiring transplantation of corneal tissue from donors. Diseases such as Fuchs' dystrophy, iridocorneal endothelial syndrome, keratoconus, lattice dystrophy, ocular herpes infections, trachoma are examples. In addition physical damage to the eye, for example chemical burns, sports injuries, and shrapnel injuries during military conflict are common due to the vulnerable nature of the eye.
Existing available surgical treatments include penetrating keratoplasty (full-thickness transplantation), anterior lamellar keratoplasty (and deep lamellar keratoplasty, which removes the epithelium and damaged stroma and spares the deepest parts of the stroma and endothelium) and endothelial keratoplasty (by which the patient's endothelium is replaced with a transplanted disc of posterior stroma/Descemet's membrane/corneal endothelium or Descemet's membrane/corneal endothelium). Although corneal transplantations are increasingly successful, there is a worldwide shortage of donor organs and current supplies cannot meet the demand. Moreover, patients with severe pathologies such as chemical burns, severe infections, autoimmune conditions, have a high risk of rejecting transplanted human donor corneas. Even allografting of a single epithelial layer from stem cells bears a lifelong risk of rejection necessitating the recipient to take expensive immune-suppressant drugs with often severe adverse side effects.
The extreme shortage of donor corneas, the high risk of rejection and infection after transplantation has led to a long felt need to design materials with cornea-like characteristics which are suitable for use as prosthetics or for implantation. Materials suitable as implants must be transparent (allowing more than 85% of light transmission), of good mechanical strength to allow handling, stable against enzymatic digestion, allow cell adhesion and migration to support regeneration. Examples of attempts to design corneal implants and prosthesis are known in the prior art.
For example, WO2006042272 discloses materials suitable to artificially replace or augment a damaged or diseased cornea comprising a hydrogel based on biocompatible polymers allowing diffusion of nutrients and improved mechanical strength. The artificial cornea also comprises molecules such as proteins and peptides, for example collagen, which are covalently linked to the surface of the hydrogel to promote epithelial cell adhesion and proliferation on the non-adhesive hydrogel surface. EP2535041 discloses an interpenetrating polymeric network of two or more polymer networks creating a hydrogel matrix wherein at least one polymer is a biopolymer such as collagen. This hydrogel is biocompatible, non-toxic and suitable for use as a scaffold for tissue regeneration. Liu et al (2009) discloses collagen phoshorylcholine interpenetrating network hydrogels as corneal substitutes. Artificial corneas, transplanted into mini-pigs, were shown to promote re-epithelialization and nerve regeneration. Others such as US2008/0287342 have developed corneal shields consisting of a network comprising collagen-mimetic peptide-PEG polymer conjugates to deliver drugs and to provide a protective environment that promotes the healing or surgical and traumatic wounds.
Although artificial corneas based on collagen are cell friendly and allow adhesion and cell proliferation they may not be suitable as a permanent implant in all patients, particularly those with very severe pathologies (e.g. chemical burns, dry eye, infections, autoimmune disease), where there is abnormal cell growth and vascularisation can reduce transparency, which can also grow into the artificial cornea when grafted into such eyes. The cornea is an avascular structure and several attempts to mimic the natural corneal characteristics through “skirt and core” matrices aimed to provide both a translucent core and an outer skirt which enables vascularisation and cell migration. For example, US2011/0125260 discloses an artificial cornea comprising a ridged translucent core and a skirt comprising a porous hydrogel, wherein the core is made by forming a hydrogel skirt around a mould wherein the mould is filled with synthetic monomers such as poly(methyl methacrylate) forming a core. The boundary of skirt/core forms an Interpenetrating network and the core is optionally covered by a bacterial resistant biofilm. The hydrogel skirt comprises biological molecules such as peptides, proteins or collagen. US2011/182968 discloses a corneal prosthesis comprising a core and skirt. The core comprises an interpenetrating network comprising PEG-DA (first network) and methacrylic acid (second network) whereas the skirt is hydrogel based and can contain biomolecules linked to it. Biomolecules such as peptides or collagen can be incorporated into the interpenetrating network of the core by forming acrylate-PEG-peptide monomers which can then be linked to PEG-DA of the first network and acrylates of the second network of the core. Myung et al (2007) discloses artificial corneas comprising a central core composed of a poly (ethylene glycol)/poly(acrylic acid) (PEG/PAA) double network with collagen type I tethered to its surface, and a micro-perforated PHEA hydrogel skirt also modified with collagen. The interpenetrating micro-perforated skirt promotes stromal tissue integration whereas the double network core supports surface epithelialization. US2014/0142200 discloses a double-crosslinked, transparent collagen material for use as an ophthalmic device, wherein the collagen is diafiltered, lyophilised, re-dissolved and homogenized and non-fibrillar to reduce small molecule contaminants and subsequently obtaining accurate collagen concentrations essential for an efficient cross-linking method.
Although collagen based interpenetrating network hydrogels are advantageous over synthetic interpenetrating network hydrogels by allowing superior cell adhesion and migration, the production of recombinant collagen is exceedingly expensive making it a less suitable alternative when considering mass production of artificial corneas. Additionally, the production of an artificial cornea comprising skirt and core structure requires several steps thus increasing the cost. Moreover, none of the above attempts to provide a replacement cornea has successfully fully integrated the artificial implant that replaces a damaged or diseased cornea with a fully functional artificial cornea. To date, clinically used prostheses are non-immune, compatible and necessitate live-long immunosupression. Furthermore, increased intraocular pressure leading to glaucoma is a severe side effect that often necessitates co-implantation of a shunt to prevent glaucoma; [see Management of Glaucoma Following Boston Keratoprosthesis: Gargi Khare Vora, Kathryn A Colby European Ophthalmic Review, 2012;6(4):214-7.
In our co-pending PCT applications, WO2015/032985, WO2015/055661 and WO2015/055656 we disclose a hydrogel, a modified hydrogel and a corneal implant respectively. The content of each PCT application is incorporated by reference in their entirety.
This disclosure relates to a hydrogel comprising a novel collagen mimetic peptide (which can also be described as a collagen-like peptide) that interlinks to form a network, which allows migration of cells and vessel ingrowth aiding regeneration into the surrounding tissue minimising the risk of rejection when used in a corneal implant. Moreover, the artificial cornea comprises a core that prevents cell and vessel ingrowth so maintaining optimal transparency. The use of the novel collagen mimetic peptide forming the network of the hydrogel is advantageous as it allows greater flexibility converting an inert polymeric backbone (plastic or biopolymer such as silk). It also significantly reduces the costs of producing artificial corneas compared to those made from recombinant human collagen due to reduction of the purification steps; and compared to extracted animal source polymers such as collagen, as well as the costs of batch-to-batch testing for pathogens to prevent transmission in extracted materials. The device is of substantial mechanical strength and elasticity allowing additional surface modification. Kits allowing tailor made skirt core matrices are also disclosed.